Observation of pseudorotamers of two unconstrained Wittig intermediates, (3RS,4SR)- and (3RS,4RS)-4-cyclohexyl-2-ethyl-3,4-dimethyl-2,2-diphenyl- 1,2λ5-oxaphosphetane, by dynamic 31P NMR spectroscopy: Line-shape analyses, conformatio

Article abstract of DOI:10.1021/ja974332o

The two typical, that is unstabilized and unconstrained, oxaphosphetane diastereomers (3RS,4SR)-(3) and (3RS,4RS)-4-cyclohexyl-2-ethyl-3,4- dimethyl,2,2-diphenyl-1,2λ⁵-oxaphosphetane (5) have been prepared selectively by deprotonation of (1RS,2

Full text of DOI:10.1021/ja974332o

J. Am. Chem. Soc. 1998, 120, 10653-10659
10653
Observation of Pseudorotamers of Two Unconstrained Wittig
Intermediates, (3RS,4SR)- and (3RS,4RS)-4-Cyclohexyl-2-ethyl-3,4-
5
31
dimethyl-2,2-diphenyl-1,2λ -oxaphosphetane, by Dynamic P NMR
Spectroscopy: Line-Shape Analyses, Conformations, and
Decomposition Kinetics
†
‡
‡
,†
†
Felix Bangerter, Martin Karpf, Lukas A. Meier, Paul Rys,* and Peter Skrabal
Contribution from the Laboratorium f u¨ r Technische Chemie, Department of Chemistry, Swiss Federal
Institute of Technology (ETH), CH-8092 Zurich, Switzerland, and Pharma DiVision, Process Research,
F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland
ReceiVed December 22, 1997
Abstract: The two typical, that is unstabilized and unconstrained, oxaphosphetane diastereomers (3RS,4SR)-
5
(
3) and (3RS,4RS)-4-cyclohexyl-2-ethyl-3,4-dimethyl-2,2-diphenyl-1,2λ -oxaphosphetane (5) have been prepared
selectively by deprotonation of (1RS,2SR)- (6) and (1RS,2RS)-(2-cyclohexyl-2-hydroxy-1-methylpropyl)-
ethyldiphenylphosphonium iodide (7). The X-ray structure analysis of 7 established the relative configurations
of 6 and 7 and consequently those of 3 and 5. Pseudorotation of the 1,2-oxaphosphetanes 3 and 5 and their
3
1
alkene formations have been studied by P NMR spectroscopy. The conformations of the resolved
1
13
pseudorotamers at the pentacoordinate trigonal bipyramidal phosphorus atom are identified by H, C, and
3
1
P NMR data. For both diastereomers, the two rotamers with equatorial position of the ethyl substituent
dominate in pseudorotation. Line-shape analyses provided the rate constants and activation parameters of
pseudorotations. The results represent the first experimental data for pseudorotation of unstabilized and
unconstrained 1,2-oxaphosphetanes. Oxaphosphetanes 3 and 5 stereoselectively decompose to (Z)- and (E)-
2
-cyclohexylbut-2-ene, respectively. At -30 °C, pseudorotations are faster than alkene formations by a factor
11
of ca. 10 , and at -20 °C, the half-life of the trans isomer 5 in alkene formation is approximately 8 times
longer than that of the cis isomer 3.
Introduction
intermediates to be identified. The analysis of the role of 1,2-
oxaphosphetanes comprises their formation, their reversal or
equilibration, their pseudorotation, and their decomposition to
alkenes for the purpose of elucidating the origin of the
stereochemistry in the Wittig reactions. The latest work involves
investigation of the thermolysis of 1,2-oxaphosphetanes, inde-
pendently of their formation, by the synthesis of isolable
The Wittig reaction for the synthesis of alkenes remains an
important tool of the chemist, not only in the laboratory, but
also for the production of alkenes on an industrial scale. In
recent reviews, Vedejs and Peterson have collected a wealth of
empirical data and have sought and followed unbroken threads
concerning mechanistic and selectivity aspects.
A central theme of mechanistic studies was and still is the
1
5
,6
oxaphosphetanes.
The pseudorotation of 1,2-oxaphosphetanes has been studied
2
detection and analysis of so-called Wittig intermediates. 1,2-
Oxaphosphetanes as intermediates in typical Wittig reactions
1
13
31
by H, C, and P NMR spectroscopy at low temperatures,
but to date, individual pseudorotamers have been resolved only
31
3
were detected by P NMR spectroscopy as early as 1973. With
7
8
9
for stabilized or constrained oxaphosphetanes. Many of these
the exception of stabilized betaines,1 they are the only
,4
(4) Recent examples: (a) Geletneky, C.; F o¨ rsterling, F.-H.; Bock, W.;
†
Swiss Federal Institute of Technology (ETH). WWW depart from
Berger, S. Chem. Ber. 1993, 126, 2397-2401. (b) Neumann, R. A.; Berger,
S. Book of Abstracts: International Symposium: The Research of Georg
WittigsReleVance to Chemistry Today, Heidelberg, July 15-18, 1997; p
42.
http://www.chem.ethz.ch.
‡
F. Hoffmann-La Roche AG.
*
To whom correspondence should be addressed.
(
1) (a) Vedejs, E.; Peterson, M. J. In AdVances in Carbanion Chemistry,
(5) (a) Kawashima, T.; Kato, K.; Okazaki, R. J. Am. Chem. Soc. 1992,
114, 4008-4010. (b) Kawashima, T.; Kato, K.; Okazaki, R. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 869-870. Review: Kawashima, T.; Okazaki, R.
Synlett 1996, 600-608.
Vol. 2; Snieckus, V., Ed.; JAI Press Inc.: Greenwich, 1996; pp 1-85. (b)
Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1-157. (c) The
reader is also referred to the comprehensive review article with more than
5
50 references by Maryanoff and Reitz: Maryanoff, B. E.; Reitz, A. B.
Chem. ReV. 1989, 89, 863-927.
2) Vedejs, E.; Marth, C. F. In Phosphorus-31 NMR Spectral Properties
(6) Isolable 1,2-oxaphosphetanes have been reported much earlier. See
refs 39 and 41 in ref 1a and ref 4 in ref 5a.
(
(7) For example: (a) Ramirez, F.; Smith, C. P.; Pilot, J. F. J. Am. Chem.
Soc. 1968, 90, 6726-6732. (b) Ramirez, F.; Pfohl, S.; Tsolis, E. A.; Pilot,
J. F.; Smith, C. P.; Ugi, I.; Marquarding, D.; Gillespie, P.; Hoffmann, P.
Phosphorus 1971, 1, 1-16.
(8) (a) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1989, 111, 1519-
1520. (b) Vedejs, E.; Marth, C. F. J. Am. Chem. Soc. 1990, 112, 3905-
3909. (c) Marth, C. F. Ph.D. Dissertation (Order No. 8826058), University
of Wisconsin, Madison, WI, 1988.
in Compound Characterization and Structural Analysis; Quin, L. D.,
Verkade, J. G., Eds.; VCH Publishers: New York, 1994; pp 297-313.
(3) (a) Vedejs, E.; Snoble, K. A. J.; Fuchs, P. L. J. Org. Chem. 1973,
3
9
8, 1178-1183. (b) Vedejs, E.; Snoble, K. A. J. J. Am. Chem. Soc. 1973,
5, 5778-5780. For the first oxaphosphetane detected from an unusual
ylide, see: Birum, G. H.; Matthews, C. N. J. Chem. Soc., Chem. Commun.
1
967, 137-138.
1
0.1021/ja974332o CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/06/1998

10654 J. Am. Chem. Soc., Vol. 120, No. 41, 1998
Bangerter et al.
Scheme 1. Pseudorotation of 1 and 1′ a
a
Estimated minimum rate constant at -83 °C, g3 × 10 s-1).8a
3
Scheme 2. Synthesis of 1,2-Oxaphosphetane 3 via
Deprotonation of the (1RS,2SR)-Hydroxyphosphonium
a
Salt 6
Figure 1. Measured (left, 202.46 MHz, 128 fids, 38.46 kHz sweep
width in 64k data points, in THF-d at -30, -70, -80, -85, -90,
8
and -95 °C, bottom to top) and calculated13 (right) P NMR spectra
31
of 3.
greater temperature dependence of the line widths of oxaphos-
phetanes 3 and 5 (e.g., at -50 °C, 19 and 21 Hz) compared to
ca. 2-14 Hz (0 to -110 °C) of 2 and 4 indicated dynamics
3
1
accessible on the P NMR time scale.
a
Cy ) cyclohexyl. KHMDS ) potassium hexamethyldisilazide. R,S
Configurations are shown. The diastereomer 5 was obtained in an
analogous manner from the (1RS,2RS)-hydroxyphosphonium salt 7.
oxaphosphetanes have been prepared as model compounds. For
5
the typical 4,4-diethyl-2-methyl-2,2-diphenyl-1,2λ -oxaphos-
phetanes (1,1′) (Scheme 1), typical in the sense of not being
stabilized by substituents which are either part of another ring
and therefore put constraints in the oxaphosphetane or are
electron-withdrawing, a minimum pseudorotation rate constant
To obtain diastereomerically pure oxaphosphetanes for DNMR
investigations, 3 and 5 were synthesized independently (Scheme
10
2
for 3). The relative configurations of the precursors 6 and 7
and consequently of the 1,2-oxaphosphetanes 3 and 5 were
confirmed by an X-ray structure analysis of 7. Deprotonation
of the phosphonium salts 6 or 7 at -78 °C in THF-d8 with
potassium hexamethyldisilazide (KHMDS) yields stereoselec-
8a
between 1 and 1′ has been estimated. We now report what is,
to our knowledge, the first kinetic analysis of the pseudorotation
of two typical, that is unstabilized and unconstrained, 1,2-
oxaphosphetanes. The compounds studied were the diastereo-
mers (3RS,4SR)- (3) and (3RS,4RS)-4-cyclohexyl-2-ethyl-3,4-
tively solutions of 3 or 5.
For 1,2-oxaphosphetane 3 the experimental 31P DNMR
5
dimethyl-2,2-diphenyl-1,2λ -oxaphosphetane (5) (as enantio-
spectra together with the calculated spectra from line-shape
meric pairs). For pseudorotation analysis as well as for the
13
analysis are shown in Figure 1. At -110 °C two peaks of
kinetic analysis of the decomposition of oxaphosphetanes 3 and
isomers A and B (A dominating) for 3 as well as for 5 are
observed (3, -63.0 (A) and -69.9 ppm (B); 5, -63.5 (A) and
5
, they have been prepared independently10 from (1RS,2SR)-
(6)and(1RS,2RS)-(2-cyclohexyl-2-hydroxy-1-methylpropyl)ethyldi-
-
70.5 ppm (B)). We interpret these observations as the result
phenylphosphonium iodide (7) (see Scheme 2 for 3).
of pseudorotation at the oxaphosphetane phosphorus atom
1
4
entailing resolvable syn and anti isomers (Scheme 3) at low
temperature. The exchange rates and populations (for 3 between
-95 and -30 °C, for 5 between -95 and -50 °C) were used
to obtain the pseudorotation rate constants (Table 1) and
Results and Discussion
31P DNMR: Line-Shape Analyses. In the course of our
study11 of the Wittig reactions of ethylidenetriphenylphosphor-
ane and ethylideneethyldiphenylphosphorane with cyclohexyl
methyl ketone, the respective diastereomeric intermediates, the
q
q
15
activation parameters ∆H and ∆S (Table 2).
1
31
16
Conformations. H (Table 3) and P NMR data of 3 and
5, as well as 13C NMR data17 as far as accessible for 3 (Table
4), are in complete agreement with data from similar 1,2-
oxaphosphetanes. The JC3,P coupling constant of 3, averaged
between A and B, is 86.7 Hz, indicating equatorial P-C3 bonds
in the trigonal bipyramidal (tbp) configuration of the phosphorus
atom. With the exception of oxaphosphetanes bearing electron-
12
cis- (2 and 3) and trans-oxaphosphetanes (4 and 5), have been
identified by 31P{ H} NMR spectroscopy (202.46 MHz, in THF-
d8; 2 and 4 at -50 °C, -64.0 and -64.7 ppm; 3 and 5 at -30
1
9
1
°
C, -65.6 and -66.8 ppm). As a consequence of the substit-
uents at C3 and C4 barriers of pseudorotation higher than
between 1 and 1′ were to be expected. Thus the significantly
(
9) For reviews, see refs 1 and 2.
(13) With WIN-KUBO, Version 951208, Bruker-Franzen Analytik
GmbH, Bremen, BRD (Kubo, R.; Tomita, K. J. Phys. Soc. Jpn. 1954, 9,
888-919. Kubo, R. J. Phys. Soc. Jpn. 1954, 9, 935-944. Sack, R. A. Mol.
Phys. 1958, 1, 163-167. Johnson, C. S., Jr.; Moreland, C. G. J. Chem.
Educ. 1973, 50, 477-483).
(14) Syn and anti refer to the positions of P-CH2CH3 and C3-CH3.
(15) Linear regression analyses of the Eyring equation gave squared
correlation coefficients of 0.9999 for 3 and 0.9993 for 5. To avoid potential
problems due to the viscosity of the solutions or to the lower solubility of
3 and 5, spectra obtained below -95 °C have been excluded from line-
shape analyses.
(10) For the elaboration of this stereoselective method starting from
oxiranes, see: Vedejs, E.; Fuchs, P. L. J. Am. Chem. Soc. 1973, 95, 822-
8
25.
(11) Meier, L. A. Ph.D. Thesis No. 12315, ETH, 1997.
12) Cis and trans refer to the positions of C3-CH3 and C4-cyclohexyl.
(
The diastereomeric ratio 2:4 (at -75 °C) is 95:5 and that for 3:5 (at -73
C) is 4:96 (in THF, with potassium hexamethyldisilazide). For the first
resolutions of diastereomeric 1,2-oxaphosphetanes, see: Reitz, A. B.; Mutter,
M. S.; Maryanoff, B. E. J. Am. Chem. Soc. 1984, 106, 1873-1875. See
also: ref 1a, pp 34-36.
°

Pseudorotamers of Unconstrained Wittig Intermediates
J. Am. Chem. Soc., Vol. 120, No. 41, 1998 10655
a
1
Scheme 3. Pseudorotational Isomers of 3 and 5 and
resemblance of the essential H NMR data of oxaphosphetanes
Tentative Assignment of Rotamers A and B
3 and 5 (Table 3) suggests that the ethyl group in the rotamers
of 5 is also in the equatorial position. Accordingly, pseudoro-
tation between the diastereomeric syn/anti-Et,Me isomers is
proposed (Scheme 3). The equatorial Et positions of 3 and 5
parallel the equatorial Me groups observed for the dominating
1
,2-oxaphosphetane rotamers 1 and 1′ (Scheme 1), the pseu-
dorotation of which is still fast at -83 °C and rotamers have
1
not been resolved (averaged JC,P ) 96.4 Hz, Table 4), and for
their dibenzophosphole (DBP) analogues 8a (slow exchange at
1
-
53 °C: JC,P ) 98.1 Hz), which show coalescence of the C3
8
a
methylene protons near room temperature. With the help of
1
9
31
the coalescence criterion, we have calculated P coalescence
temperatures of -89 and -92 °C for 3 and 5, respectively.
The rotamers A of 3 and 5 dominate at low field in the 31P
spectra. Only a tentative assignment of A and B to the syn
and anti rotamers can be made according to Scheme 3, since
neither any relevant J coupling constants from H or
spectra nor any NOE enhancements in the H spectra are
accessible. Force field geometry optimizations, however,
a
Cy ) cyclohexyl. Only the 3S,4R- and 3R,4R pair, respectively,
are shown.
A B
Table 1. Pseudorotation Rate Constants k and k
(10 s-1, A is
3
A
the Main Isomer) and Population of A (p ) of 3 and 5 (T in °C)
3
1
13
C
3
5
20
21
1
2
2
T
k
A
k
B
p
A
k
A
k
B
p
A
2
3
starting from 50-100 conformations (generated by random
walk) to avoid local minima, suggest assigning the major
rotamers A to the 3-anti and 5-syn pairs: the calculated energy
-
95
90
85
80
75
70
50
0.284
0.667
1.64
0.986 0.776
1.06
2.51
5.40
11.5
23.8
43.2
-
-
-
-
-
-
-
2.23
5.32
11.06
0.770
0.764
0.759
3.51
-1
differences (3.1 kJ mol for 3 and 1.0 for 5) between syn and
anti pairs (3S,4R and 3R,4S of 3, 3R,4R and 3S,4S of 5) with
15.6
46.4
0.748
0.713
regard to trend correspond to the experimental energy differ-
599
q
-1
ences obtained from line-shape analysis (∆∆H of 1.8 kJ mol
30 1997
4960
for 3 and 0.6 for 5 (Table 2)).
Pseudorotation. From kinetic and thermodynamic arguments
it follows that the isomerizations of 1,2-oxaphosphetanes 3 and
1
withdrawing substituents on the P atom, JC3,P coupling constants
2
of 76-88 Hz have been reported.
1
13
From the JC,P coupling constants in CH3[ C]H2-labeled 3,
obtained with CH3[ C]H2I ( C ) 99.4%, Scheme 2), it is
deduced that in both rotamers of 3 the ethyl substituent is also
in the equatorial tbp position. The JC,P coupling constants at
110 °C are 106.8 Hz in the dominating (A at δC ) 35.6 ppm)
and 92.4 Hz in the minor rotamer (B at 21.5), both values being
in the typical range found for equatorial sp carbons. At -30
C an averaged value of 95.6 Hz (30.5 ppm) is observed. The
calculated population averaged value (pA ) 0.713, Table 1),
however, is 102.7 Hz. The difference of ca. 7 Hz could indicate
that the third rotamer with the ethyl group in apical tbp position,
7b,24
5
are the consequence of pseudorotations in turnstile
or
13
13
25
Berry permutation processes and not of acid-catalyzed ring
opening (“irregular process”
7b,24
via the protonated betaine).
1
First, isomerizations via the polar protonated betaines would
be expected to exhibit negative ∆S values due to the reduction
of freedom of the solvent induced by its reorientation toward
the polar protonated betaines. Second, the available acid
-
q
3
2,8b
26
°
(
19) Shanan-Atidi, H.; Bar-Eli, K. H. J. Phys. Chem. 1970, 74, 961-
9
63. Martin, M. L.; Delpuech, J.-J.; Martin, G. J. Practical NMR
Spectroscopy; Heyden & Son, Ltd.: London, 1980; pp 295-297.
1
(20) At -110 °C in the H spectrum, the lines are too broad, and in the
13
1
13
accessible C spectra, the concentrations are too low to observe H, C or
which is not populated to a detectable extent at low temperature,
even 13C, C J coupling constants in the rotamers of CH3[ C]H2-labeled
13
3
13
makes a minor contribution18 at temperatures above the fast
3.
exchange limit.
1
1
(
21) H, H-NOE enhancements have contributed to the identification of
8
b
1
It is reasonable to assume an analogous disposition of the
oxaphosphetane ring in the diastereomer 5, and the very close
the pseudorotamers of the dibenzophosphole-oxaphosphetane 8b. The H
lines of the oxaphosphetanes 3 and 5 at -90 to -110 °C, however, are too
broad for NOE experiments (and in part there is overlap of the relevant
1
(
16) All NMR data were taken in THF-d8, chemical shifts (δ, ppm)
relative to internal TMS ( H, C) and external 85% aqueous H3PO4 ( P),
coupling constants in hertz; for P data, see text. All H coupling patterns
have been analyzed by iteration with the program WIN-DAISY, Version
.0, Bruker-Franzen Analytik GmbH, Bremen, BRD, 1995.
17) Owing to the limited solubility of 6 and 7 and therefore relatively
resonances with cyclohexyl signals). For the same reasons H chemical shift
1
13
31
arguments, as applied to 8b, also cannot be used for 3 and 5. But the
3
1
1
1
following argument regarding the H chemical shifts observed at -30 °C
supports the tentative assignment. The only significant difference between
1
3
the H spectra of 3 and 5 is an upfield shift of 0.44 ppm observed for the
(
CH3-C4 group in 5 (1.21 and 0.77 ppm, respectively). Since the CH3-C4
groups in 3B and 5B clearly are positioned in the shielding region of the
equatorial free rotor P-phenyl substituent (force field geometry optimiza-
tions2 ), this upfield shift is likely to reflect the higher population of the
rotamer 5B compared to 3B (Table 1).
low concentrations of 3 (saturated and filtered solution, <49 mM) and 5 (7
1
3
mM), the essential C data have been obtained only for 3 at -30 °C, for
the dominating rotamer 3A at -100 °C (minor rotamer B not observable),
2,23
1
3
and for both rotamers of CH3[ C]H2-labeled 3 (20 mM) at -110 °C.
1
2
(
18) Assuming a typical apical coupling constant JC,P of 15 Hz, the
contribution of the population of the third rotamer at -30 °C would be ca.
%. Additional indications for a small contribution also come from small
differences between measured and calculated population averaged chemical
(22) For MM+ force fields in the program HyperChem 5.0 (Hypercube
Inc., Waterloo, Canada) the MM2 parameters and atom types (Allinger, N.
L., 1991) with the 1977 functional form (Allinger, N. L. J. Am. Chem. Soc.
1977, 99, 8127-8134. Burkert, U.; Allinger, N. L. Molecular Mechanics;
ACS Monograph 177; American Chemical Society: Washington, DC, 1982)
are used.
8
13
31
shifts of the ethyl-[ C]H2 group (30.5-31.6 ) 1.1 ppm) and of P (-65.6
3
1
-
(
-65.0 ) 0.6 ppm). Temperature effects on the P shifts are negligible
31
e.g., the P shift of 2 is constant from -110 to -30 °C within 0.1 ppm)
(23) In the program ChemPlus (Version 1.5, Hypercube Inc., Waterloo,
Canada), an Extension for HyperChem.
13
22
but cannot be excluded for C shifts because at low temperature a distinction
between temperature shifts and shifts which are due to observation of the
(24) Ramirez, F.; Ugi, I. AdV. Phys. Org. Chem. 1971, 9, 25-126.
17
dominating rotamer only (concentration of 3 too low to observe the minor
(25) Berry, R. S. J. Chem. Phys. 1960, 32, 933-938.
1
3
(26) As negative activation entropies (ca. -24 and -44 J mol K-1
)
-1
rotamer except its CH2 group in C-labeled 3) is impossible. Since the
third rotamer is not detectable at low temperature, a three-site exchange
analysis is not possible. Nevertheless, this uncertainty does not call into
question the principal results presented herein.
have been observed for the second step of the Wittig reaction, the first-
order thermolysis of the isolable oxaphosphetanes 9a5a and 9b, slightly
polar transition states have been postulated.
5b

10656 J. Am. Chem. Soc., Vol. 120, No. 41, 1998
Bangerter et al.
Table 2. Activation Parameters of Pseudorotation of 3 and 5 (∆H and ∆G in kJ mol , ∆S in J mol K-1
q
q
-1
q
-1
)
q
q
q
q
q
a
q b
∆
H
A
∆H
B
∆S
A
∆S
B
∆G
A
∆G
A
3
5
47.3 ( 0.6
44.5 ( 1.4
45.5 ( 0.6
43.9 ( 1.4
72.0 ( 3.2
66.9 ( 7.1
72.0 ( 3.2
66.8 ( 7.0
35.6 ( 1.1
33.6 ( 2.6
29.1 ( 1.4
27.5 ( 3.2
a
At -110 °C. b At -20 °C.
1
) of 3 and 5 (Multiplicities in Brackets)16
CH
-P (ethyl, ddq)a
Table 3. Essential H NMR Data (500.14 MHz, at -30 °C, in THF-d
8
H-C
3
(dq)a
H
3
C-C
3
(dd)
H
A
B
H
3
C (ethyl, ddd)
δ
2JH,P
3JH,H
δ
3JH,P
3JH,H
δ
2JH,P
2JH,H
3JH,H
δ
3JH,P
3JH,H
3
5
4.31
22.8
7.9
1.07
27.0
7.9
1.95
6.5
13.8
7.0
12.3
12.3
13.0
13.0
7.8
7.7
7.6
7.3
1.07
20.2
7.8
7.7
7.6
7.3
2
.35
2.08
.48
4.18
22.2
7.8
0.92
26.9
7.8
1.05
20.3
2
13.0
a
(δ ) 3.56, 2JH,P ) 16.4), CH
-P (δ ) 1.91, 2JH,P ) 13.7).8a
For comparison, 1 and 1′ at -83 °C, in toluene-d
8 2
: H C
3
3
1
3
1
16,17
Table 4.
C{ H} NMR Data
), of Rotamer 3A (at -100 °C) and Available Data of
of 3 (125.77 MHz, at -30 °C,
entropies have been attributed either to the “unfavorable, but
in THF-d
8
inevitable equatorial-equatorial disposition” of one of the two
8
a
1
8
,1′ (at -53 °C, in Toluene-d )
bidentate ligands in the transition state or to hexacoordinate
C
3
C
4
P-CPh
P-CH a
2
7b,24
transition states (i.e., permutation in an “irregular process”
),
δ
1JC,P
δ
2JC,P
15b
69.3 14.0
δ
1JC,P
δ
1JC,P
depending on the donative properties of the solvents. But
similar solvent effects have not been observed for corresponding
66.9b
1
3
3
,c 1′ 60.3 83.0
148.8 70.5 24.4
96.4
95.6
3
1
d
d
d
d
pentacoordinate phosphorus compounds. The common struc-
68.7 86.7
-
-
-
30.5
35.6 106.8
Ae 64.9 ca. 91 70.2 ca. 12
-
f
f
tural feature of the oxaphosphetanes 8a,b, of the stiborane, and
32
of bis(2,2′-biphenylylene)selenurane and -tellurane, in which
a
. b Reference 1a, p 19 and ref 2, p 302. c CH
: δ 24.6, 11.2, 8.5 (JC,P ) 15.0, 7.1, 5.9).
In 1 and 1′: P-CH
-C , CH -CH
Cyclohexyl: CH δ 27.4, 27.7, 27.8, 27.9, and 30.9 and CH 45.5. For
the CPh atoms, neither the slow (very broad not assignable lines at -100
C) nor the fast exchange limit has been reached. At -30 °C: six sharp
Ph δ 127.7-133.8 (JC,P ) 1.8-10.8) and two broad P-CPh δ ca. 148.5
3
3
-
q
-1 -1
nearly zero or negative ∆S values (5.9 to -43.9 J mol K )
have also been observed for the pseudorotations, is the presence
of one or two bidentate ligands. Therefore, it is likely that the
C
4
, CH
3
3
3
2
d
2
°
C
q
smaller positive (or nearly zero) to negative ∆S values of
1
e
pseudorotations of oxaphosphetanes 8a,b and of the selenurane
and telurane have to be attributed to strain induced by the
diequatorial position of a bidentate ligand in the intermediate
and 144.5 (partly averaged JC,P of ca. 45 and 80). CH
CH -CH
3 4 3 3
-C , CH -C ,
3
2
: δ 24.6, 11.8, 7.2 (JC,P not resolved). Cyclohexyl: CH δ
2
f
13
2
3
7.1, 27.3, 27.6, 27.7, and 30.7 and CH 44.6. At -110 °C, C-labeled
1
, B at 21.5 ( JC,P ) 92.4).
33
rotamer of pseudorotation, which has to be traversed in the
3
4
equilibrium between the populated rotamers. Since there is
(
hexamethyldisilazane from KHMDS, see Scheme 2) is a
relatively weak acid (pKa,THF ) 25.8 ) and therefore catalytic-
ally inefficient.
The positive ∆S values of pseudorotation of 3 and 5 (Table
) are in accord with the positive, but smaller ∆S values of
.5 and 18.0 (( 16.7) J mol K , respectively, for the
pseudorotations of the 1,2-oxaphosphetanes 8a and 8b, both
no bidentate ligand in the 1,2-oxaphosphetanes 3 and 5, their
27
q
positive ∆S values do not contradict the observed smaller or
negative activation entropies of the other permutation processes.
q
q
Comparison of the rate constants kA and kB of pseudorotation
2
5
3
-1
-
1
-1
of 3 and 5 at -85 and -80 °C (1.64 to 16.3 × 10 s , Table
1) with the estimated minimum rate constant (g3 × 10 s ) at
83 °C of oxaphosphetanes 1 and 1′ suggests that pseudoro-
3
-1
8c
8b
8
a
-
tation between 1 and 1′ might be at least a power of 10 faster.
The pseudorotation rate constant of 8a, the DBP analogue of 1
3
-1
and 1′, at 43 °C (5.6 × 10 s ) is very close to the rate constants
kB of 3 and kA of 5 at -85 °C, that is at a temperature ca. 120°
q
-1 8c
lower. The activation enthalpies ∆H of 8a (56.5 kJ mol )
8
b
-1
and 8b (66.5) compared to 43.9-47.3 kJ mol of 3 and 5 in
part reflect the stabilization by the bidentate ligand, again
understood in terms of the strained intermediate rotamer with a
3
3,34
diequatorial disposition of the phosphole ring.
Considering
(30) We thank a reviewer for drawing our attention to this paper. For
pseudorotation of 10-P-5 spirophosphoranes, see: Kojima, S.; Kajiyama,
K.; Nakamoto, M.; Akiba, K.-y. J. Am. Chem. Soc. 1996, 118, 12866-
1
2867. For hexacoordinate 1,2-oxaphosphetanides, see: Kojima, S.; Akiba,
with the dibenzophosphole ring incorporated as a stabilizing
bidentate ligand.28 However, a number of negative activation
K.-y. Tetrahedron Lett. 1997, 38, 547-550, and Kawashima, T.; Watanabe,
5
K.; Okazaki, R. Ibid. 1997, 38, 551-554. For pseudorotation of a 1,2λ -
azaphosphetidine, see: Kawashima, T.; Soda, T.; Okazaki, R. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1096-1098.
-1
-1
entropies (-26.4 J mol
K
in n-octane to -101.7 in pyridine)
have been reported for the permutation process between two
(31) Footnote 18 in ref 29: Kojima, S.; Nakamoto, M.; Kajiyama, K.;
Akiba, K.-y. Unpublished results.
diastereomeric 10-Sb-5 stiboranes.2 These negative activation
9,30
(32) Ogawa, S.; Sato, S.; Erata, T.; Furukawa, N. Tetrahedron Lett. 1992,
(
27) Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem. 1985, 50,
232-3234.
28) The bidentate DBP ligand stabilizes the oxaphosphetanes 8a,b by
increasing the activation barriers of pseudorotations as well as of
33, 1915-1918.
3
(33) Assuming the turnstile mechanism, in 1,2-oxaphosphetanes this less
stable rotamer has the P-O bond in the unfavorable equatorial position.
Originally it had been postulated as a necessary intermediate in the alkene
formation step: Bestmann, H. J. Pure Appl. Chem. 1979, 51, 515-533.
See, however, the discussions in refs 1a and 8a.
(
1
a
decompositions.
29) Kojima, S.; Doi, J.; Okuda, M.; Akiba, K.-y. Organometallics 1995,
4, 1928-1937.
(
1
(34) Reference 1a, pp 46-48.

Pseudorotamers of Unconstrained Wittig Intermediates
J. Am. Chem. Soc., Vol. 120, No. 41, 1998 10657
Table 5. Rate Constants of Alkene Formation of 3 and 5
rate constant substituted from the first-order rate equation (40
and 53 degrees of freedom for 3 and 5, respectively).
(T in °C)
38
a
b
a
b
T
k
(3)
k
(5)
T
k
(3)
k
(5)
In agreement with the findings for all the oxaphosphetane
3
9
-
-
-
5
4
4
-5
-4
cis-trans pairs investigated, the cis-oxaphosphetane 3 de-
composes faster than the trans-oxaphosphetane 5 (Table 5). At
-20 °C the half-life of the trans isomer 5 is approximately 8
times longer than that of the cis isomer 3 (Table 6). The
activation entropies are identical within the confidence limits,
-
-
-
30
25
20
4.38 × 10
1.09 × 10
2.64 × 10
-15
-10
7.74 × 10
1.82 × 10
-5
3.18 × 10
a
s-1 ( 1.2-1.9%.
b
-1
s
( 2.0-3.0%.
q
Table 6. Activation Parameters of Alkene Formation of 3 and 5
a result which is plausible for two diastereomers. ∆H is 4.6
q
q
-1
q
-1
-1
(
∆H and ∆G in kJ mol , ∆S in J mol
K
)
-1
kJ mol higher for the trans isomer 5, understood in terms of
q
q
∆Gq a
a,b
∆
H
∆S
t
1/2
stronger nonbonded interactions in the cis isomer 3.
The isomers 3 and 5 (in THF-d8) at -20 °C have a 25.6 and
3
5
89.7 ( 1.5
94.3 ( 1.2
At -20 °C. b In minutes.
42.5 ( 5.8
43.1 ( 4.5
78.96 ( 0.04
83.40 ( 0.06
44
363
-1
q
21.2 kJ mol lower ∆G than the dibenzophosphole-oxaphos-
8
a
phetane 8a at 43 °C (104.6, in CD2Cl2), since 8a is stabilized
a
q
by the bidentate DBP ligand. The activation enthalpies ∆H
-
1 5a
of the isolable oxaphosphetanes 9a (121.8 kJ mol ) and 9b
the different substitution patterns at P, C3, and C4 in oxaphos-
phetanes 1, 1′, 3, 5, and 8a,b, the stabilization by the DBP ring
in two otherwise identically substituted oxaphosphetanes such
as 1, 1′, and 8a is expected to be even more apparent.
In the 13C spectra of oxaphosphetanes 8d,e at -83 °C or
above only one set of signals has been observed, indicating either
a single pseudorotamer or rapid interconversion.8 In view of
the available data of 3, 5, and 8a,b the detection of one strongly
dominating pseudorotamer of 8d and of 8e seems to be more
a
3
5
plausible.
Decomposition Kinetics. The decomposition rates were
measured independently from the formation of the oxaphos-
phetanes via deprotonation of 6 and 7 at -78 °C and following
the decrease of 3 and 5 by 31P NMR spectroscopy. Alkene
formations from cis- (3) and trans-1,2-oxaphosphetane 5 are
first-order in 3 and 5 and stereoselective: 3 decomposes (within
(102.1,5b both in toluene-d8) with the Martin ligand are 32.1
-
1
q
and 12.4 kJ mol higher than ∆H of oxaphosphetane 3 and
-1
27.5 and 7.8 kJ mol higher compared to 5. The stability of
the oxaphosphetanes 9 is due to the CF3 groups, to the Martin
ligand, or to both as electron-withdrawing substituents. The
oxaphosphetane 9b is less stable owing to the ester group in
the 3-position. By analogy with the arguments regarding the
positive activation entropies of pseudorotation, the positive ∆Sq
values of alkene formation from 3 and 5 indicate nonpolar
transition states. Considering the Martin ligand and the electron-
attracting substituents in the oxaphosphetanes 9 in comparison
to the methyl and cyclohexyl groups in 3 and 5, this is in
1
31
the detection limit of H and P spectroscopy) exclusively to
Z)- and 5 exclusively to (E)-2-cyclohexylbut-2-ene.36 With
regard to the selectivity of alkene formation in the lithium-free
(
1
31
Wittig reaction we have verified by H and P spectroscopy
(
and by crossover experiments11 with [1,1,2,2,2- H5]diethyldi-
2
phenylphosphonium bromide) that the diastereomers 3 and 5
do not equilibrate. The kinetically formed 3/5 ratio determines
the Z/E ratio37 (ca. 1:9) of 2-cyclohexylbut-2-ene.
q
understandable contrast to the negative ∆S values of slightly
2
6
polar transition states as postulated for 9a,b.
Since only three temperature points are available for 3 as
well as for 5 (allowing only one degree of freedom for the
Pseudorotation versus Decomposition. In typical 1,2-
oxaphosphetanes pseudorotation is much faster than decomposi-
tion. For example, the rate constants (partly extrapolated, Tables
1 and 5) at -30 °C of oxaphosphetane 3 differ by approximately
q
Student factor), the error in the activation parameters ∆H and
q
∆
S from conventional linear regression analysis of the Eyring
equation would be large and the differences between the
activation parameters of alkene formation from 3 and 5 not
significant. Therefore, to obtain activation parameters as precise
as possible for comparison with available data of constrained
and stabilized or isolable 1,2-oxaphosphetanes, the rate constants
and activation parameters (Tables 5 and 6) have been evaluated
by iterative nonlinear modeling of the Eyring equation with the
1
0
11
11
5 × 10 (kA) and 1 × 10 (kB) and of 5 by 9 × 10 (kA) and
1
2
1 × 10 (kB). Therefore, as in the case of other oxaphosphe-
8
,34
tanes reported, the pseudorotations of 3 and 5 do not control
the alkene formation steps. For 1 and 1′ at -10 °C a factor of
8
10 has been estimated by a comparison with the decomposition
rate of the cis-diphenyl analogue of 8d (Ph2 instead of DBP).8c
Extrapolations of the rate constants of 3 and 5 to -10 °C give
(
35) For 8d this has been suggested to explain the temperature
1
dependence of the H spectra between -78 and 63 °C. A second rotamer
(38) Available experimental data: 15 data points at each temperature
(-30, -25, -20 °C) for 3; 25 data points (-20 °C), 13 (-15), 20 (-10)
for 5. The experimental errors of the 31P peak integrals have been assumed
to be normally distributed with a variance independent of time and
temperature. In addition to the enthalpies and entropies of activation, the
initial integral value at each temperature has been treated as adjustable
parameter (allowing 45 - 5 degrees of freedom for 3, 58 - 5 for 5). The
confidence intervals for the adjusted parameters have been obtained
according to a scheme extending the classical linear approach to an iterative
nonlinear approach. For one of the first applications to NMR spectroscopic
data, see: Leipert, T. K.; Marquardt, D. W. J. Magn. Reson. 1976, 24,
181-199 and references therein. Supporting Information is available.
(39) Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Inners, R. R.; Almond,
H. R., Jr.; Whittle, R. R.; Olofson, R. A. J. Am. Chem. Soc. 1986, 108,
7664-7678. See also: ref 1a, pp 37-39. Recent examples: Yamataka,
H.; Takatsuka, T.; Hanafusa, T. J. Org. Chem. 1996, 61, 722-726.
3
1
was also not detected in the P spectra. Reference 8c, pp 155-157.
(
36) Both isomers are known compounds. (a) E isomer: Danheiser, R.
L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176-1185. (b) Z and E
isomers: Vedejs, E.; Cabaj, J.; Peterson, M. J. J. Org. Chem. 1993, 58,
6
509-6512.
37) The initial diastereomeric oxaphosphetane ratio 3:5 is 4:96. Stereo-
(
chemical equilibration during alkene formation is not significant: the Z/E
ratio of the alkene after 100% conversion is 8:92 (reaction time 45 h at
-
73 °C and 1 h during warming to room temperature). In analogy to our
observations (Ph3PdCHCH3 is Z-selective, EtPh2PdCHCH3 is E-selective;
see footnote 12), the reagent control of the Z/E selectivity in the lithium-
free Wittig ethylidenation of a variety of ketones, including cyclohexyl
methyl ketone, has been reported by Vedejs and co-workers for the ylides
Ph3PdCHCH3 and EtDBPdCHCH3 (Z/E of 2-cyclohexylbut-2-ene 78:22
3
6b
and 4:96, respectively).

10658 J. Am. Chem. Soc., Vol. 120, No. 41, 1998
Bangerter et al.
9
11
factors between ca. 9 × 10 (kA of 3) and 2 × 10 (kB of 5) by
which pseudorotations are faster than alkene formation. Since
the decomposition rate constants of 3 and the above analogue
-
3
of 8d at -10 °C are nearly identical (1.39 × 10 and 1.3 ×
-
3
1
0 ) and the pseudorotation rate constant between 1 and 1′ is
at least an order of magnitude greater than the rate constants of
and 5, it is very likely that the pseudorotation of 1 and 1′ is
3
1
2
approximately 10 times faster than decomposition.
Bidentate ligands, as for example in dibenzophosphole-
oxaphosphetanes, increase the activation barriers of both
processes to different extents. A typical case is the constrained
DBP analogue 8a8 of 1 and 1′ with a ratio of rate constants of
suggest that for the 1,2-oxaphosphetanes 10 it may be possible
to obtain kinetic data for both pseudorotations and decomposi-
tions. A comparison with the data for 3 and 5 would then make
it possible to quantify the effects of constraints imposed by the
dibenzophosphole ring on both activation barriers in the
a
8
pseudorotation to decomposition of ca. 10 at 43 °C. The very
unstable dibenzophosphole-oxaphosphetane 8c4 (Cy )
cyclohexyl), an ester-substituted analogue of 8a, exemplifies
the critical influence of this type of substituent and demonstrates
that decomposition can become faster than pseudorotation. For
0
44
oxaphosphetanes.
Conclusions
8
c, which could not be detected at a temperature below -80
In summary, apart from the estimations for the intermediates
1 and 1′, the rate constants and activation parameters provided
for the pseudorotation of the diastereomeric 1,2-oxaphosphetanes
3 and 5 and for their alkene formation constitute the first
experimental data for two typical, that is unconstrained and
unstabilized, Wittig intermediates. They reveal the order of
magnitude that the rate constant of pseudorotation can be greater
than that of decomposition. The comparison with available data
of constrained, stabilized, or destabilized 1,2-oxaphosphetanes
demonstrates the different extents to which the activation barriers
of both processes independently become increased or decreased
by substituents.
°
1
C, decomposition at -70 °C has been estimated to be at least
0 times faster than pseudorotation.34
The bidentate Martin ligand in constrained and stabilized
oxaphosphetanes such as 9a,b is a special case with respect to
activation barriers of decomposition as well as of pseudorotation.
Analogous to the monodentate (CF3)2CHO group,24 in combina-
tion with additional electron-withdrawing (e.g., CF3) or conju-
gating (e.g., Ph) groups, it stabilizes the oxaphosphetanes to
such an extent that they may become isolable. At the same
time the activation barrier of pseudorotation of such oxaphos-
phetanes increases since the higher-energy intermediate rotamer
has the Martin ligand in a strained diequatorial location and
The conformations of two dominating rotamers in both
pseudorotations have been identified, and the stereoselective
alkene formation from oxaphosphetanes 3 and 5 has been
ascertained by NMR spectroscopy.
33
both P-O bonds are thus in an unfavorable equatorial position.
And as for 8c, the activation barrier of decomposition may be
decreased to below the barrier of pseudorotation by an ester
group at C3. But decomposition for its part occurs in a far higher
temperature region. One typical case is the 3-methoxycarbo-
Experimental Section
5b
nyl-oxaphosphetane 9b, for which between ca. 69 and 111
C only alkene formation has been observed.41,42 The important
common feature of 8c and 9b is the ester substitution in the
NMR Spectroscopy. All experiments were performed on a Bruker
°
AMX-500 spectrometer with samples in dry, peroxide-free THF-d
8
under argon. Temperature control and calibrations were achieved with
a Bruker variable-temperature Unit B-VT 1000E and a Pt-100 sensor
3
-position, which is known to facilitate bond cleavage in
1a
decomposition.
(
(0.1 °C, Degussa AG). See the Supporting Information for key
The comparison of the oxaphosphetanes 3 and 5 with 1, 1′
and its DBP analogue 8a and with the very unstable oxaphos-
phetane 8c exemplifies that particularly the separation of
constraint by bidentate ligands from stabilization or destabiliza-
tion by substituents in pairs of closely related 1,2-oxaphosphe-
tanes will provide further insight into the dependence of the
relative heights of pseudorotation and decomposition barriers.
original spectra and details.
Syntheses. The preparations of 3, 5, 6, 7, and precursors, including
spectroscopic data, are described in the Supporting Information.
Acknowledgment. We thank Dr. Martin Badertscher (Labor-
atorium f u¨ r Organische Chemie, Department of Chemistry,
ETH) for the nonlinear modeling, Dr. Michael Hennig and Peter
Sch o¨ nholzer (F. Hoffmann-La Roche AG) for the X-ray
structure analysis, and F. Hoffmann-La Roche AG for financial
support.
36b
In this respect the DBP analogue 10a of 3 and 5 and the two
1
,2-oxaphosphetanes 10b,c40 (Cy ) cyclohexyl) are very
interesting candidates. To our knowledge, 10b is the structurally
closest analogue mentioned in the literature of the oxaphos-
phetanes 3 and 5, and 10c is its DBP analogue. Apart from
Supporting Information Available: X-ray structural infor-
mation on 7 (crystal data, ORTEP drawing, table of bond lengths
and bond angles), details of NMR spectroscopy (THF-purifica-
tion, T1 relaxation times, sample preparations, typical sample
concentrations and acquisition parameters, parameters of the
analyses of decomposition kinetics of 3 and 5, calculation of
the alkene E/Z ratios formed from 10a3 and 10c, no data
6b
43
seem to be available. The results of Vedejs and Marth for the
1
,2-oxaphosphetanes 1, 1′ and 8a and our results for 3 and 5
(
(
(
40) Vedejs, E.; Fleck, T. J. J. Am. Chem. Soc. 1989, 111, 5861-5871.
41) Reference 5b, footnote 11.
1
42) For decomposition at 120 °C of two stable (CF3)2CHO-substituted
coalescence temperatures, complete lists of H NMR data of 3,
1,2-oxaphosphetane rotamers without pseudorotation (except by an irregular,
5
, and (E)- and (Z)-2-cyclohexylbut-2-ene), synthetic procedures
catalyzed process), see: Ramirez, F.; Smith, C. P.; Pilot, J. F. J. Am. Chem.
Soc. 1968, 90, 6726-6732. See also: refs 7b and 24. However, fast
pseudorotation at room temperature and a slow one at -30 °C of an
analogous oxaphosphetane with a second (CF3)2CHO group has been
observed since one of the three P-O bonds is always in an apical position:
Gibson, J. A.; R o¨ schenthaler, G.-V.; Schmutzler, R. Z. Naturforsch. B 1977,
1
3
for 6, C-labeled 6, 7, and the 2-cyclohexyl-2,3-dimethylox-
iranes (including general methods and analytical data), key
(44) C. F. Marth has discussed ring and steric effects on the pseudoro-
tation of a large number of pentacoordinate phosphorus compounds, but
experimental data of 1,2-oxaphosphetanes are still scarce. See ref 8c, pp
171-179.
3
2, 599-600.
(43) Vedejs, E.; Marth, C. Tetrahedron Lett. 1987, 28, 3445-3448.

Pseudorotamers of Unconstrained Wittig Intermediates
J. Am. Chem. Soc., Vol. 120, No. 41, 1998 10659
1
31
original NMR spectra ( H of 3 and 5 at 243 K; P of 3, 5, and
and by iterative nonlinear modeling (in all 21 pages, print/PDF).
See any current masthead page for ordering information and
Web access instructions.
1
3
13
31
C-labeled 3 at 163 K; C of labeled 3 at 163 K; P DNMR
of 3 and 5 measured and calculated in the line-shape analyses),
and comparison of rate constants and activation parameters of
decomposition of 3 and 5, obtained by linear regression analyses
JA974332O